ASH Highlights on NK cells: a new frontier for cancer immunotherapy

Dr Evren Alici, principal researcher and head of the cell and gene therapy group at the Karolinska Institute in Stockholm, Sweden was so kind to summarise data on NK cell therapy covered during the ASH 2023 congress and to share his insightful perspectives on future developments within the realm of NK cell therapies.

In recent years, significant strides have been made in the realm of NK cell-based therapies, particularly evident in the notable increase in newly registered clinical trials focusing on haematological indications. Despite the ongoing assessment of clinical outcomes, a growing body of evidence indicates the potential efficacy of NK cell-based therapy when utilized as a standalone treatment. Notably, this effectiveness has been observed across a spectrum of NK cell products, whether they undergo genetic modifications or not.

Several promising strategies have emerged in recent discussions, notably checkpoint strategies, which have shown considerable promise in improving the survival rates of patients previously deemed difficult to treat effectively. Additionally, novel approaches, such as retargeted NK cells, CAR modified NK cells and TCR modified NK cells were presented. Of particular interest is the TCR modified approach, which involves engineering NK cells to target neoantigens or neoepitopes, effectively endowing them with dual functionality. Moreover, the potential for abrogating escape mechanisms presents a powerful tool in this context. Furthermore, there has been exploration into new targeting antigens using CAR technology. However, persisting challenges include ensuring the sustained functionality and in vivo expansion of these engineered cells. Consequently, the focus has shifted towards enhancing the retention of function and prolonging the survival of these cells within the patient, with the ultimate goal of achieving more effective treatments and exploring longitudinal potential for combination therapies. The integration of NK cell-based therapies with various treatment modalities is garnering increasing attention within the scientific community. Particularly notable is the exploration of NK cell-based therapies in conjunction with NK cell engagers or combinations of cytokines. This synergistic approach holds significant promise for enhancing therapeutic efficacy.

Prof dr Katy Rezvani’s presentation during the award ceremony underscored the immense potential inherent in NK cells and the possibility of further engineering these cells to achieve complete tumour eradication. While ongoing clinical trials are yet to reach completion, the preliminary results appear promising. The talk served as a source of inspiration, highlighting the pivotal importance of addressing the challenge of cell persistence. Numerous research groups are actively engaged in tackling this hurdle, recognizing that in the NK cell field, persistence correlates with increased anti-tumour activity and retention of function within the tumour microenvironment. Moving forward, the focus will likely be on two key breakthroughs: enhancing the functionality of NK cells within the tumour microenvironment and prolonging their persistence. With a plethora of promising approaches currently under investigation, there is hope that one or more of these strategies will emerge in the near future, heralding a new era in NK cell-based therapies.

Our research group is pioneering the exploration of universal grafts, which differs from conventional approaches in the field. Our focus lies in disrupting the immunological synapse from the host while preserving the host’s immune function. One notable challenge we encounter is the limitation imposed by the preconditioning of patients. Many individuals excluded from our studies due to frailty are unable to tolerate the lymphodepletion regimens, or preconditioning, necessary for conventional approaches. Addressing this challenge is paramount for our work. We aim to engineer NK cells capable of retaining functionality while ensuring the integrity of the host immune system. This endeavour represents a novel direction in immunotherapy, holding promise for extending treatment options to a broader patient population.

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